The present invention relates to a composite material which is especially useful to repair bone in joints and other load bearing positions.
Operations to replace defective hip joints are now well-known and are performed routinely in the United Kingdom and western world and total hip arthroplasty (THA) is currently one of the most successful operations performed. The operation involves the removal of the patient""s defective hip joint and its complete replacement with a prosthetic joint. The patient""s quality of life is generally greatly improved throughout the time period that the prosthetic joint remains functional, and from the Swedish hip register the success rate at ten years post operatively lies at around 90%. Total knee arthroplasty is fast approaching similar levels of success. However, a major disadvantage of the prosthetic joint is its finite lifetime and the ultimate need for replacement of the prosthetic. The limitation on the lifetime of the prosthetic arises when the articulating surfaces become worn and debris from the worn prosthetic attracts a macrophage response. Chemicals released by the macrophages unfortunately tend to cause degradation of the bone around the prosthetic implant site, causing loosening of the prosthetic joint which can be difficult to combat. The success rate of subsequent revision hip surgery is significantly lower than for primary THA.
Various approaches have been made to overcome the bone defect around a hip joint. Examples include the use of a large custom-made prosthesis, but this is an expensive approach and has yielded poor results.
Autograft would provide the best bone for re-incorporation in impaction grafting, but donor site morbidity usually prevents harvesting autograft from an individual at the same time as performing their revision hip surgery. Femoral heads removed at the time of primary hip surgery are a ready, sterile supply of allograft, which is the next most preferable graft type. The immunogenic incompatibility between donor and recipient is not usually a problem and is further attenuated by the act of freezing. The increased demand and the move for centres to perform their own revision operations has prompted many smaller centres to set up facilities to perform their own bone banking of allograft femoral heads at the time of primary hip arthroplasty.
Cadaver allografts have also been used to pack the bone defect and ideally large amounts of bone could be harvested in a clean manner from cadaveric donors and then sterilised. However allografts carry a high risk of disease transmission (eg HIV and CJD) and those from cadavers often fail to incorporate into the host skeleton, proving to be of limited value. Nonetheless, utilisation of allograft bone is increasing as the number of revisions of failed joint arthroplasty rises and techniques for bone replacement gain wider acceptance. Future demands for allograft bone are expected to rise as the number of primary joint arthroplasties performed per annum increases and this will be further exacerbated as operations are offered to younger patients and the population as a whole, live longer. Current estimates place the total number of hip replacements performed world wide as over 800,000 per annum.
There is therefore a large and increasing demand for stores of bone graft.
Bone graft alone, either morcellised or whole, has had some success in replacing lost bone stock. However, limited supply and increasing concerns regarding transmission of pathogens has prompted interest in synthetic materials. There has been an increasing interest in bone substitute materials, although their current use and future role have yet to be defined, together with cost-benefit analysis.
Inert materials with high mechanical strength have been tested clinically. Apatite-wollastonite (A-W) glass ceramic has been used in combination with milled allograft and fibrin glue with some success in revision THA""s. Direct bonding between bone and A-W glass ceramic granules was seen histologically. There is however no replacement of the inert material with time to replace lost bonestock, should a subsequent revision be necessary. Interest in bio-active materials has evolved to address this problem. Osteogenic Protein-1 (BMP-7) (Stryker Biotech) is a growth factor in the TGF-xcex2 superfamily and has been shown to stimulate bone producing cells in vitro and in vivo. It may also enhance bone incorporation around implants, whereas Hydroxyapatite (HA) may be an alternative to bone allograft. Pro-Osteon has been investigated as a bone void filler in several studies.
It is an object of the present invention to provide a material suitable for packing bone defects, for example in any fractured or broken bone, including facial bone, the jaw and teeth. The material is especially useful for packing bone defects in load bearing positions such as in primary joint arthroplasties (for example around prosthetic hip or knee joints) whilst simltaneously enabling bone regeneration to occur within the treated defect.
In one aspect, the present invention provides an admixture of biocompatible water-soluble glass (BWSG) particles and morsellised bone particles, wherein the particle size range and particle size distribution is pre-selected to be capable of forming an aggregate. The particle distribution may be selected according to the Fuller curve for maximal packing of particles.
Critically we have found that addition of BWSG, either as a bulking agent in a 50/50 mix by volume or by adding the particle size(s) needed to achieve the Fuller requirements, increases the shear strength of the bone. Desirably at least 10% by volume, more usually 25% or 40% by volume, of BWSG is present in the mixture.
As an example, the admixture may comprise particles of diameter 0.1 mm to 10 mm, preferably 0.2 mm to 8 mm, especially preferably 0.5 mm to 6 mm.
Where the diameters of the majority of the particles fall within the preferred range of 0.5 mm to 6 mm, the following typical particle distribution (which conforms to the Fuller curve) would produce a well-graded mixture:
particles 6.0 mm to 5.0 mm=7.0%
particles 5.0 mm to 4.0 mm=9.0%
particles 4.0 mm to 3.0 mm=11.5%
particles 3.0 mm to 2.5 mm=7.5%
particles 2.5 mm to 2.0 mm=9.0%
particles 2.0 mm to 1.5 mm=11.5%
particles 1.5 mm to 1.0 mm=16.5%
particles 1.0 mm to 0.5 mm=28.0%
The admixture of the present invention exhibits excellent mechanical stability and are able to xe2x80x9ccementxe2x80x9d the prosthesis into healthy bone tissue in a manner similar to a bridge pile sunk into a gravel aggregate.
Improved results have been obtained where the bone particles are washed before use. We believe that washing removes the xe2x80x9cwet slurryxe2x80x9d produced due to increased fat and marrow release in finely ground bone particles. The presence of xe2x80x9cwet slurryxe2x80x9d decreases the shear strength of the composite.
The critical properties of the aggregate formed by the admixture are particle size distribution, angle of internal friction, dilatancy and degree of fluid saturation. The fluid may be any sterile fluid (such as water or a protein solution) but advantageously may contain soluble growth factors able to promote bone repair and/or certain bone stem cells or tissue engineered bone forming cells.
To produce the strongest aggregate (or aggregate most resistant to shear stress), the material of the present invention should have the following characteristics;
1. xe2x80x9cIdealxe2x80x9d particle size distribution;
2. Low state of Hydration;
3. Sequential layered impaction of well mixed material;
4. Impacted with a large amount of Joules/Volume; and
5. Rigidly contained (use of Meshes).
xe2x80x9cIdealxe2x80x9d particle size distribution refers to a mixture of different particle sizes that produces the strongest aggregate. As explained above, this has been determined by Fuller who mathematically determined the graphical curve (Fuller Curve) of particle distribution that represents the sequence of spheres to fit the xe2x80x9cgapsxe2x80x9d which if carried to infinitely small sizes of spheres will allow a pyramid to be constructed. When considering irregularly shaped particles, where there is not an infinite supply of ever diminishing particle sizes, it is accepted practice to use a linear log of the range of available sizes, to determine an ideal mixture.
Experts in Soil Mechanics have found that the mechanical properties of any collection of particles, or xe2x80x9caggregatexe2x80x9d is dependent upon the particle size distribution, and not on the individual properties of the particle. The particle size distribution of all test materials in this project was therefore determined using sieve analysis.
The Linear Log Line (rather than the Fuller Curve) has certain advantages in experimental use for two main reasons:
1. Fuller is based upon packing of xe2x80x9cspheresxe2x80x9d, which is quite different from sharp or angular particles.
2. The Linear Log straight line is considered to represent xe2x80x9cwell gradedxe2x80x9d soils in civil engineering (i.e. that a large distribution of particle sizes is present). Well graded soil will attain larger densities on compaction than others and therefore will be more resistant to shear. As current bone mills produce a finite range of particle sizes (xcx9c5 mm to xcx9c0.3 mm), drawing a straight line between the two sizes on the log plot is the best in a xe2x80x9csoil mechanicsxe2x80x9d sense.
Also of note, is that in theory, Fuller requires almost 30% of its particle sizes below the minimum currently produced by bone mills. This means that by using Fuller""s curve, there may even be loss of strength. Using a second mill to produce the very small particles may potentially block the interstices of the graft and interfere with the neovascularisation of impacted graft. Notwithstanding the above, a derived mixture (based on Fuller, mathematically determined as 34% 3 mm Aesculap mill+66% 6 mm Aesculap mill) was produced, compacted and shear tested.
Our studies have shown that:
1. Well-graded aggregates of saturated allograft bone/BWSG will not differ in stress/strain behaviour under compaction.
2. Well-graded aggregates of saturated allograft bone/BWSG will not differ in speed and quality of reincorporation in a sheep limb bone defect model.
3. Well-graded aggregates of saturated allograft bone/BWSG will not differ in reincorporation or in mechanical stability over a twelve month period in a sheep hip replacement model.
Preferably the water-soluble glass controllably releases calcium and/or phosphate moieties and dissolves steadily over a time period appropriate to bone repair. The inclusion of the glass is envisaged to promote healthy bone growth more effectively than achievable using only morsellised bone particles. In one embodiment other active ingredientsxe2x80x94especially those able to combat infection or disease or to promote healthy bone growthxe2x80x94may be controllably released as the water-soluble glass dissolves. Particular mention may be made of growth factors active in bone tissue and of bone stem cells or tissue engineered bone forming cells.
In a further aspect, the present invention provides a method of repairing defective bone in a load-bearing position, said method comprising compacting an admixture as described above into the bone defect.
In one embodiment, the bone defect comprises the area around a prosthetic (especially a prosthetic hip joint) damaged by macrophage activity.
Phosphorous pentoxide (P2O5) is preferably used as the glass former of the biodegradable glass used in the admixture.
Generally the mole percentage of phosphorous pentoxide in the glass composition is less than 85%, preferably less than 60% and especially between 30-60%.
Alkali metal""s, alkaline earth metals and lanthanoid oxides or carbonates are preferably used as glass modifiers.
Generally, the mole percentage of alkali metals, alkaline earth metals and lanthanoid oxides or carbonates is less than 60%, preferably between 40-60%.
Boron containing compounds (eg B2O3) are preferably used as glass additives.
Generally, the mole percentage of boron containing compounds is less than 15% or less, preferably less than 5%.
Other compounds may also be added to the glass to modify its properties, for example SiO2, Al2O3, SO3 sulphate ions (SO42xe2x88x92) or transition metal compounds (eg. first row transition metal compounds).
Typically the soluble glasses used in this invention comprise phosphorus pentoxide (P2O5) as the principal glass-former, together with any one or more glass-modifying non-toxic materials such as sodium oxide (Na2O), potassium oxide (K2O), magnesium oxide (MgO), zinc oxide (ZnO) and calcium oxide (CaO). The rate at which the glass dissolves in fluids is determined by the glass composition, generally by the ratio of glass-modifier to glass-former and by the relative proportions of the glass-modifiers in the glass. By suitable adjustment of the glass composition, the dissolution rates in water at 38xc2x0 C. ranging from substantially zero to 25 mg/cm2/hour or more can be designed. However, the most desirable dissolution rate R of the glass is between 0.01 and 2.0 mg/cm2/hour.
The water-soluble glass is preferably a phosphate glass, and preferably comprises a source of silver ions which may advantageously be introduced during manufacture as silver orthophosphate (Ag3PO4). The glass preferably enables controlled release of silver or other metal ions, for example Zn, Cu, Mg, Ce, Mn, Bi, Se and Cs (preferably Ag, Cu, Zn and Mg) and other constituents in the glass and the content of these additives can vary in accordance with conditions of use and desired rates of release, the content of silver generally being up to 5 mole %. While we are following convention in describing the composition of the glass in terms of the mole % of oxides, of halides and of sulphate ions, this is not intended to imply that such chemical species are present in the glass nor that they are used for the batch for the preparation of the glass.
The optimum rate of release of the metal ions (eg Ag, Cu, Zn or Mg, or any of the other metal ions mentioned above) into an aqueous environment may be selected by circumstances and particularly by the specific function of the released metal ion. The invention provides a means of delivering metal ions to an aqueous medium at a rate which will maintain a concentration of metal ions in said aqueous medium of not less than 0.01 parts per million and not greater than 10 parts per million. In some cases, the required rate of release may be such that all of the metal added to the system is released in a short period of hours or days and in other applications it may be that the total metal be released slowly at a substantially uniform rate over a period extending to months or even years. In particular cases there may be additional requirements, for example it may be desirable that no residue remains after the source of the metal ions is exhausted or, in other cases, where the metal is made available it will be desirable that any materials, other than the metal itself, which are simultaneously released should be physiologically harmless. In yet other cases, it may be necessary to ensure that the pH of the resulting solution does not fall outside defined limits.
Generally, the mole percentage of these additives in the glass is less than 25%, preferably less than 10%.
In a preferred embodiment the BWSG comprises 20-35 mole % Na2O; 18-30 mole % CaO and 45-60 mole % P2O5.